Molecular Targets in T Lineage Leukemia

T 系白血病的分子靶点

基本信息

批准号：
8091575
负责人：
Monique Dail
金额：
$ 14.92万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-19 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8091575
关键词：
1-Phosphatidylinositol 3-Kinase Accounting Acute Lymphocytic Leukemia Acute T Cell Leukemia Acute leukemia Address Adolescent Adult Age Aggressive course Alleles Award Biochemical Biochemical Genetics Biochemical Pathway Biological Markers Candidate Disease Gene Cell Line Cells Chemotherapy-Oncologic Procedure Child Chronic Myeloid Leukemia Clinical Clinical Trials Design Cloning Complex Data Dexamethasone Drug Combinations Drug Delivery Systems Drug resistance FBXW7 gene Foundations Genes Genetic Genetic Heterogeneity Goals Growth Health Homeostasis Human In Vitro Incidence Insertional Mutagenesis Knowledge Laboratory Research Lead Learning Lesion Life Lymphoid MEKs Malignant Neoplasms Mediating Mentors Modeling Molecular Molecular Target Mus Mutate Mutation NOTCH1 gene Oncogenic Outcome Pathogenesis Pathway interactions Patients Phase Phosphatidylinositide 3-Kinase Inhibitor Precursor T-Lymphoblast Proteins Reagent Refractory Relapse Research Project Grants Resistance Resources Retroviridae Risk Sampling Signal Transduction Signaling Pathway Gene Site Specimen Survivors T-Cell Transformation T-Lymphocyte Subsets Techniques Testing Therapeutic Therapeutic Agents Time Training Treatment Failure Tumor-Derived Virus Work anticancer research base cancer cell career cohort drug leukemogenesis drug sensitivity experience high risk human disease improved in vivo inhibitor/antagonist insight leukemia leukemogenesis mouse model mutant neoplastic cell new therapeutic target novel novel therapeutics pre-clinical preclinical study resistance mechanism response secretase small molecule tool treatment strategy tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer of immature T lymphoblasts for which current therapies are highly toxic and ineffective in many patients. The precedent of imatinab in Chronic myelogenous leukemia (CML) demonstrates the great potential of drugs that target molecular lesions specific to cancer cells. T-ALL patients frequently have genetic alterations that activate the Ras/PI3K/Akt pathway and Notch1, thus testing inhibitors of these pathways is a high priority. In addition, greater understanding of the molecular and biochemical basis of T lineage leukemic growth will likely reveal novel drug targets. Retroviral insertional mutagenesis (RIM) is a powerful strategy for introducing genetic alterations that can be traced and identified. I previously used RIM to find genes that cooperate with oncogenic K-Ras (KrasG12D) to induce acute leukemia. Infecting KrasG12D mice with the MOL4070 retrovirus resulted in a high incidence of T-ALL that frequently harbored somatic Notch1 mutations as well as diverse genetic lesions generated by RIM. Using this strategy, I have generated a cohort of 70 primary transplantable T-ALLs that display remarkable biochemical and genetic heterogeneity thereby recapitulating the diversity observed in human cancer. The overall goals of this K99/R00 proposal are to test treatment strategies that target T-ALL molecular lesions in vivo, analyze acquired drug resistance, and uncover genes and biochemical pathways that underlie T cell transformation two specific aims: 1) To investigate the effects of a small molecule inhibitor of PI3K alone or in combination with other therapeutic agents on leukemic growth in vivo and to identify genes that modulate drug sensitivity and resistance; 2) To identify mechanisms of Notch1-independent growth in T-ALL. This K99/R00 award will provide me with the resources, time and training necessary to apply the T-ALL model I have developed to important preclinical and mechanistic questions. It will allow me to transition into the field of translational cancer research and generate data and reagents that will be the foundation for my own independent research laboratory. This award will enable me to achieve the following career goals: 1) Develop knowledge and experience in preclinical trial design and application; 2) Learn techniques to manipulate primary murine cells; and 3) Gain experience working with human patient samples. During the mentored phase I will conduct several preclinical trials, determine biomarkers of therapeutic response, investigate resistance mechanisms to a PI3 Kinase inhibitor, and identify genes/signaling pathways deregulated in T-ALLs that lack active Notch1. During the independent phase I will evaluate and validate resistance to drug combinations, validate molecules/pathways that substitute for active Notch1, and test therapies directed at novel drug resistance and leukemogenesis pathways I identify in Aims 1 and 2. Overall these studies will test novel therapeutic strategies and identify new drug targets leading to improved treatment options for T-ALL patients. PUBLIC HEALTH RELEVANCE: T cell acute lymphoblastic leukemia (T-ALL) is a high risk and aggressive cancer for which treatments are largely unsatisfactory. The goals of this project are to use mouse T-ALLs that accurately model human disease to test novel therapies that eradicate tumor cells more effectively, to determine what causes treatment failure and relapse, and to study different subsets of T-ALL to identify new drug targets. Important insights gained in mice will be thoroughly evaluated in human cancer cells. These studies will lead to improved treatments for T-ALL patients.

描述（由申请人提供）：T细胞急性淋巴细胞白血病（T-ALL）是一种未成熟T淋巴细胞的侵袭性癌症，目前的疗法对许多患者来说具有剧毒且无效。伊马替那治疗慢性粒细胞白血病（CML）的先例证明了针对癌细胞特异性分子病变的药物的巨大潜力。 T-ALL 患者经常发生激活 Ras/PI3K/Akt 通路和 Notch1 的基因改变，因此测试这些通路的抑制剂是当务之急。此外，进一步了解 T 系白血病生长的分子和生化基础可能会揭示新的药物靶点。逆转录病毒插入诱变（RIM）是引入可追踪和识别的遗传改变的强大策略。我之前使用 RIM 寻找与致癌 K-Ras (KrasG12D) 协同诱导急性白血病的基因。用 MOL4070 逆转录病毒感染 KrasG12D 小鼠会导致 T-ALL 的高发病率，这种 T-ALL 经常带有体细胞 Notch1 突变以及 RIM 产生的多种遗传损伤。利用这一策略，我生成了 70 个原代可移植 T-ALL 队列，它们表现出显着的生化和遗传异质性，从而概括了在人类癌症中观察到的多样性。该 K99/R00 提案的总体目标是测试体内针对 T-ALL 分子病变的治疗策略，分析获得性耐药性，并揭示 T 细胞转化背后的基因和生化途径，有两个具体目标：1) 研究效果PI3K小分子抑制剂单独或与其他治疗剂联合使用对体内白血病生长的影响，并鉴定调节药物敏感性和耐药性的基因； 2) 确定T-ALL 中Notch1 独立生长的机制。该 K99/R00 奖项将为我提供必要的资源、时间和培训，以将我开发的 T-ALL 模型应用于重要的临床前和机制问题。它将让我过渡到转化癌症研究领域，并生成数据和试剂，这将成为我自己的独立研究实验室的基础。该奖项将使我能够实现以下职业目标：1）发展临床前试验设计和应用方面的知识和经验； 2）学习操作原代小鼠细胞的技术； 3) 获得处理人类患者样本的经验。在指导阶段，我将进行多项临床前试验，确定治疗反应的生物标志物，研究 PI3 激酶抑制剂的耐药机制，并确定缺乏活性 Notch1 的 T-ALL 中失调的基因/信号通路。在独立阶段，我将评估和验证对药物组合的耐药性，验证替代活性 Notch1 的分子/途径，并测试针对我在目标 1 和 2 中确定的新型耐药性和白血病发生途径的疗法。总的来说，这些研究将测试新型疗法策略并确定新的药物靶点，从而改善 T-ALL 患者的治疗选择。公众健康相关性：T 细胞急性淋巴细胞白血病 (T-ALL) 是一种高风险、侵袭性癌症，其治疗方法基本上不能令人满意。该项目的目标是利用小鼠 T-ALL 准确模拟人类疾病，测试更有效地根除肿瘤细胞的新疗法，确定导致治疗失败和复发的原因，并研究 T-ALL 的不同子集以确定新药目标。在小鼠身上获得的重要见解将在人类癌细胞中得到彻底评估。这些研究将改善 T-ALL 患者的治疗。